Jan. 5, 1952
257
NOTES
Anal. Calcd. for CIOHILNO,: C, 57.41; H, 5.30. Found: C, 57.39; H, 5.20. Methyl 3,4-Dimethoxy-5-nitrocinnamate.-A solution of 7.0 acid1* in 120 ml. of a g. of 3,4-dimethoxy-5-nitrocinnamic saturated solution of methanolic hydrogen chloride was allowed to stand until separation of a yellow solid occurred. This was removed, washed with water and recrystallized from methanol. There was zbtained 3.5 g. (48%) of creamy white crystals, m.p. 105-106 . Anal. Calcd. for C12Hl3KO6: C, 53.92; H, 4.87. Experimental7 Found: C, 54.22; H, 4.70. Methyl 2-(2'-Methoxy-rl'-methylphenyl)-l-cyclohexeneMethyl 3,4-Dimethoxy-S-aminohydrocinnamateHydrocarboxylate (I).-In accordance with the method of Canter chloride (III).-A solution of 10.0 g. of methyl 3,4-dimethand Robinson,8 14.3 g. of 3-methyl-7,8,9,10-tetrahydro-6- oxy-5-nitrocinnamate in 100 ml. of methyl acetate was subdibenzopyr~ne~ was dissolved in a boiling solution of 100 tnl. of methanol and 100 ml. of 20% aqueous sodium hy- jected t o low pressure hydrogenation using Adams catalyst. Four molar equivalents of hydrogen were rapidly absorbed. droxide. The solution was cooled t o 50' and 60 g. of di- After of the catalyst and solvent, the residue was methyl sulfate was added slowly with stirring followed by taken removal up in ether and treated with dry hydrogen chloride. 200 ml. of a 20% sodium hydroxide solution. An additional 30 g. of dimethyl sulfate was then added dropwise, This caused the separation of 8.9 g. (92%) of hygroscopic the solution was made basic and the mixture was extracted white crystals, m.p. 208-208" dec. Attempts t o convert I11 to I V by the usual procedures with ether. After the ethereal extract had been washed with water and dried. the ether was removed and the residue through the diazonium salt yielded only black intractable was distilled yielding 11.0 g. (62%) of a light yellow oil; tars. Anal. Calcd. for CIzHtsNO&l: C, 52.27; H, 6.57. b.p. 165-175' a t 5 mm., ?ZZ7D1.5465. Anal. Calcd. for C16H~~03: C, 73.84; H , 7.69. Found: Found: C, 52.87, 51.60; H, 6.30, 6.21. C, 73.70; H , 7.71. DEPARTMENT OF CHEMISTRY 2-(2 '-Methoxy-4'-methylphenyl)-cyclohexenecarboxylic UNIVERSITY O F ROCHESTER NEWYORK RECEIVED SEPTEMBER 19, 1951 Acid.-A solution of 4.0 g. of I in 30 ml. of methanol con- ROCHESTER, taining 5.0 g. of potassium hydroxide was boiled under reflux for two hours. When the cold reaction mixture was acidified with dilute hydrochloric acid, a white solid separated. This, on recrystallization from an ethanol-water Certain Derivatives of 2,s-Dihydroxyphenylacetic mixture, gave 3.0 g. (85%) of white crystals, m.p. 175-176". Acid Anal.10 Calcd. for C~aH1803:C, 73.17; H, 7.32. Found: BY R. W. BOST"AND C. A. HOWE C, 73.12; H, 7.35. Methyl 2-(2',4'-Dimethoxyphenyl)-cyclohexenecarboxylSince 2,5dihydroxybenzoic acid, gentisic acid, ate (II).-This was prepared in the same manner as described for I. From 6.0 g. of 3-hydroxy-7,8,9,10-tetrahy- has been reported to exhibit anti-rheumatic activity, 1 dr0-6-dibenzopyrone)~ there was obtained 2.5 g. (39%) of i t seemed desirable to establish whether 2,5-dia light yellow oil, b.p. 175180' at 5 mm. hydroxyphenylacetic acid, homogentisic acid, and Anal. Calcd. for CNHZOO~: C, 69.53; H , 7.21. Found: certain of its derivatives showed similar action. C, 69.01; H, 7.06. 2,5-Dimethoxyphenylaceticacid was synthesized Attempts t o obtain a condensation of either I or I1 with ethyl cyanoacetate under the usual conditions of the Michael through the Willgerodt reaction from 2,5-dimethcondensation*I were entirely unsuccessful and resulted in oxyacetophenone by the procedure of Abbott and recovery of starting material. Also, hydrogen cyanide would Smith.2 Similar procedures were utilized to synnot add t o I. thesize the 2,5diethoxy-, 2,5-di-n-propoxy- and 3-Methoxy~-hydroxy-S-nitrocinnamic Acid.-A solution 2,5-di-n-butoxyphenylacetic acids. The amides of 32.5 g. of 5-nitrovanillin,12 88.0 g. of malonic acid and 2 ml. of piperidine in 100 ml. of dry pyridine was heated on the and methyl esters of these four 2,5-dialkoxyphenylsteam-bath for three hours, and then poured into a mixture of acetic acids were prepared by standard procedures. 100 g. of cracked ice and 80 ml. of concd. hydrochloric acid. 2,5-Dihydroxyphenylacetic acid was synthesized The dark yellow solid, which separated, was washed with by the demethylation of 2,5-dimethoxyphenylacetic water and recrystallized from ethanol, There was ob;ained acid2 and also by the method of McElvain and 36.0 g. (91%) of light yellow crystals, m.p. 230-231 . ~ intermediate 2,5-dialkoxyacetopheAnal. Calcd. for CtoHsNOe: C, 50.25; H, 3.76; neut. C ~ h e n . The equiv., 119. Found: C, 50.36; H, 3.80; neut. equiv., nones were prepared from the appropriate 1,4124. dialkoxybenzene by Friedel-Crafts acylation. 3-Methoxy4-hydroxy-5-~ocinnmicAcid.-A solution The molar refractions of the 2,5-dialkoxyacetoof 10.O g. of 3-methoxy4-hydroxy-5-nitrocinnamicacid in 150 ml. of absolute ethanol was subjected t o hydrogenation phenones and methyl 2,5-dialkoxyphenylacetates in the presence of Raney nickel catalyst a t room tempera- show a considerable and fairly constant exaltation. ture and 3 atm. pressure of hydrogen. Three moles of hyNone of the compounds tested exhibited apprecidrogen was readily absorbed (90 min.). After removal of able anti-rheumatic activity. the catalyst and concentration of the solvent, there separated 8.3 g. (95%) of white crystals, m.p. 185-186'. Experimental Attempts t o convert this product to the corresponding 2,5-Dialkoxyacetophenones.-The general method of phenol, 3-methoxy4,5-dihydroxycinnamic acid, by means of the diazonium salt gave only intractable tars. Also at- Abbott and Smitha f o r the preparation of 2,Mimethoxytempted hydrogenation to the corresponding hydrocinnamic acetophenone by the Friedel-Crafts acylation of 1,4-diacid, using Raney nickel catalyst in the presence of base, methoxybenzene was used. In the case of the di-n-propoxp- and di-n-butoxy-compounds, better yields were obfailed. tained if the aluminum chloride complex was hydrolyzed (7) Analyses by Mrs. G.L. Sauvage. three hours after combination of the reactants was com( 8 ) F. W. Canter and R . Robinson, J . Chcm. Soc., 1 (1931). pleted rather than allowing the mixture to stand overnight.
the synthesis of I11 was attempted for this purpose, it was found that vanillin could be converted by the successive steps of nitration, condensation with malonic acid, and reduction to 111, but that I11 could not be successfully diazotized to yield IV. However, other approaches utilizing coumarins for the synthesis of colchicine analogs are under investigation.
19) €1. K. Sen and U. Basu, J . Indian Chcm. SOC.,6 , 467 (1928). (10) We are indebted to Mr. Nicholas Parente for the first preparation of this compound. (11) R. Connor and W.R. McClellan, J . Org. C h c n ~ .8, , 570 (1939).
(12) K.H. Slotta and G . Szyska, Bcr., 68, 184 (1935).
*
Deceased.
(1) K. Meyer and C. Ragan, Sciencc, 108, 281 (1948). (2) L. DeF. Abbott and J. D. Smith, J . B i d . Chcm., 119, 365 (1949). (3) S. M. McElvain and H. COheh, THISJOURNAL., 64, 264 (1942).
Nolgs
258
VOl. 74
TABLE I Alkoxy groups
General name
I CHaO
Yield,
%
68 52
B.p., or crystn. solv.
Mm.
OC.
OC.
Molecular formula
Analyses, 70 Carbon Hydrogen Calcd. Found Calcd. Found
2 1 " ~ CioHlrOa ~ 41" CiaHisOi 2,5-Dialkoxyacetophenone 63 71.1 70.8 8.53 8.67 19' CirHZoOa 72 26' CiaHtrOs 72.7 72.6 9.15 9.08 64 123h CioHiz0, 37 64.3 7.22 7.25 89 Ci2HisO4 64.3 2,5-Dialkoxyphenylaceticacid Or:?: 63 66 Ci4HmO4 66.6 66.3 7.99 8.17 n-C&sO 29 53 C i s H ~ 0 4 68.6 68.5 8.63 8.44 CHaO 82 133 CloH1,OsN 31.8' 32.1' 7.18' 7.01k CiHoO 70 111 CizHir01N 6.28' 6.1gk 2,5Dialkoxyphenylacetamide n-CsH7O 88 115 CicHziOsN 5.57' 5.55' n-CcHpO 86 88 CIEHIIO~N 5.02k 4.99' CHlO 93 3 44' CiiHicOi GHsO 69 2 CisHisO4 65.5 65.0 7.60 7.54 Methyl 2,5-dialkoxyphenyln-CsH70 &2 134 2 Ci5H2204 67.6 67.3 8.32 8.40 acetate n-C4H9On 50 178 18' Ci7H2804 69.4 69.2 8.90 9.24 3 a Uncorrected; lower limit of 2 degree range listed. * Taken in apparatus calibrated with standard ocompounds. Freezing point. Lit.: 20-22" (ref. 4). e Lit.: 42' (ref. 4.) f 2,4-Dinitrophenylhydrazone, m.p. 107 . Anal. Calcd. for C20H2tOsNc: N, 13.45. Found : N, 13.68. 0 2,4-Dinitrophenylhydrazone, m.p6 I16 '. Anal. Calcd. for C Z ~ H Z ~ O S N ~ : N, 12.61. Found: N, 12.61. Lit.: 123-124' (ref. 2). Pet. ether, b.p. 60-90 Methoxyl. Nitrogen %. Lit.: Did not solidify after 4 hr. in Dry Ice-bath. 45" (ref. 5). n% 1.4954. CzHsO n-GHid n-CcHoO' CH:O
{
i
116 129 138 152 Water 37% EtOH Pet.' 30% EtOH Water Water CoHrPet.' COHO-Pet.' 128 127
M.p.,b
0
Y
3 2 2
.
TABLE I1 Alkoxy
T,
groups
OC.
CHIO X-CaH?O n-c4HoO
ntD
dti
Molar refraction Founds Calcd.8
2,5-Dialkoxyacetophenones 20 1.5430 1.1401* 49 82 25 1.5150 1.0368 68 72 30 1.5067 1.0076 78.07
48 77" 67 24" 76 47'
Methyl 2,5-dialkoxyphenylacetates 64.38 63.57 25 1.5070 1.0997 C2HrO n-C:H?O 25 1.4991 1.0564 74.05 72.81 From Lorentz-Lorenz equation. Lit.: 1.1385(ref. 4). e Includes exaltation of 0.69 for conjugation of carbonyl and aromatic double bonds. The yields, physical constants and analyses are listed in Tables I and 11. 2,s-DialkoxyphenylaceticAcids.-The general method of Abbott and Smith* for the preparation of 2,5-dimethoxyphenylacetic acid from 2,5-dimethoxyacetophenone by the Willgerodt reaction was used. In the case of the di-n-propoxy- and di-n-butoxy-compounds, acidification of the basic hydrolysis solution yielded a dark oil which was dissolved in ether and extracted repeatedly with potassium bicarbonate solution followed by acidification of the aqueous extracts. The yields, physical constants, analyses and crystallization solvents are listed in Table I. 2,s-DinIkoxyphenylacetamides.-One-tenth of a mole of the 2,5dialkoxyphenylacetic acid and 22 ml. of thionyl chloride were refluxed for 30 minutes. The resulting solution was poured slowly into 100 ml. of ice-cold concentrated ammonium hydroxide. The crude product was filtered off and recrystallized. The yields, physical constants, analyses and crystallization solvents are listed in Table I. Methyl 2 ,S-Dialkoxyphenylacetates.-One-tenth of a mole of the 2,5-dialkoxyphenylacetic acid and 22 ml. of thionyl chloride were refluxed for 30 minutes. Then 150 ml. of absolute methanol were added dropwise with cooling. After addition was complete, the reaction mixture was allowed t o stand at room temperature for 30 minutes and then refluxed for 30 minutes. Excess volatile reagents and by-products were removed by evaporation, and the residual oil was fractionated twice through a 15-cm. Vigreux column. (4) I. M. Heilbron and H, M. Bunbury. "Dictionary of Organic Compounds," Vol 111, Oxford University Press, New York, N. Y., 1938,p. 568. ( 5 ) I b i d . , Vol. 11, p. 194. (6)H. Gilman, "Organic Chemistry," 2nd ed , John Wiley and Sons, Inc , New York, N. Y.,1943, p. 1751.
f
The yields, physical constants and analyses are listed in Tables I and 11. 2,s-Dihydroxyphenylacetic Acid.-This compound was prepared in a yield of 76% by the demethylation of 2,543methoxyphenylacetic acid2 and in yields of 3 8 4 7 % by the condensation of +quinone with ketene diethylacetal followed by hydrolysis.3
Acknowledgments.-The authors are indebted to The Wm. S. Merrell Co., Cincinnati, Ohio, for a grant in support of this work and for the pharmacological testing of some of the compounds synthesized, and to the Tennessee Eastman Corporation, Kingsport, Tennessee, for a generous supply of the 1,4-dialkoxybenzenes used as starting materials. VENABLECHEMICAL LABORATORY UNIVERSITY OF NORTHCAROLINA CHAPELHILL, NORTHCAROLINARECEIVED JULY 23, 1951
The Preparation of Di- and Triphenylacetonitrile and Their Cuprous Halide Complexes BY WALTERM. BUDDEAND SYLVESTER J. POTEMPA
Although a good preparation for diphenylacetonitrile (11) has been describedl it was decided to attempt a method which would involve fewer time-consuming steps and no lachrymatory intermediates. The process developed was the reaction of benzhydryl bromide (I) with anhydrous cuprous cyanide. (CaH&CHBr f CuCN ---f (CaH&CHCN I I1
+ CuRr
I was prepared in 70-75y0 yield by the action of phosphorus tribromide on benzhydrol. Heating I with a slight molar excess of oven-dried cuprous cyanide a t 125' produced pure I1 in 7 5 4 0 % yield after distillation. It was noticed that if impure I was used there was a pronounced tendency to form a stable complex molecule, 111, dec. pt. 155'. (1) C. Robb and E. Schultz,
Oyg
Synlhesrs, 28, 55 (1948).
